Genetic Variant NM_001455.4:c.32T>G (chr6-108561240-T-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_001455.4(FOXO3):c.32T>G(p.Leu11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,412,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FOXO3
NM_001455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.888

Publications

1 publications found

Variant links:

Genes affected

FOXO3 (HGNC:3821): (forkhead box O3) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

FOXO3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38798982).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXO3	NM_001455.4 link	c.32T>G	p.Leu11Arg	missense_variant	Exon 1 of 3	ENST00000406360.2	NP_001446.1	O43524-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXO3	ENST00000406360.2 link	c.32T>G	p.Leu11Arg	missense_variant	Exon 1 of 3	1	NM_001455.4	ENSP00000385824.1		O43524-1
FOXO3	ENST00000343882.10 link	c.32T>G	p.Leu11Arg	missense_variant	Exon 2 of 4	1		ENSP00000339527.6		O43524-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000354

AC:

AN:

1412056

Hom.:

Cov.:

AF XY:

0.00000572

AC XY:

AN XY:

698698

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31678

American (AMR)

AF:

0.00

AC:

AN:

37770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25114

East Asian (EAS)

AF:

0.00

AC:

AN:

36656

South Asian (SAS)

AF:

0.00

AC:

AN:

80590

European-Finnish (FIN)

AF:

0.0000206

AC:

AN:

48430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1089276

Other (OTH)

AF:

0.00

AC:

AN:

58474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000659

AC:

AN:

151736

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41302

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67920

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;D

Eigen

Benign

0.035

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.42

.;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.39

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.9

L;L

PhyloP100

0.89

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.84

N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.57

T;T

Polyphen

0.91

P;P

Vest4

0.39

MutPred

0.13

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.95

ClinPred

0.16

GERP RS

2.4

PromoterAI

-0.096

Neutral

(source)

Varity_R

0.30

gMVP

0.32

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001455.4:c.32T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over